More on SAMHD1 and HIV Infection.
In 2011, sterile alpha motif and HD domain 1 (SAMDH1) was described as the restriction factor that blocks HIV-1 replication in myeloid cells (1, 2). However, its precise mode of action remained to be found. In a paper published online in Nature Immunology on February 12, a group of international researchers shed light on this mechanisms (3). We have asked to Florence Margottin-Goguet, one of the corresponding authors of this article, a few questions.
The first line of defense to be triggered against viruses is the intrinsic immune system (4). It includes proteins that detect the presence of the assailant pattern recognition receptors (PRRs), as well as restriction factors like TRIM5alpha, APOBEC3G and thetherin. SAMHD1 is the most recently discovered restriction factor which is highly expressed in myeloid cells. Vpx,which is encoded by HIV-2, is able to bypass this block to viral replication in myeloid cells. HIV-1, however, lacks Vpx.
Alain Lafeuillade: Could you describe and explain the mechanisms you have deciphered?
Florence Margottin-Goguet*: We have deciphered how SAMHD1 inhibits HIV replication in macrophages. We have shown that SAMHD1 depletes the levels of dNTPs (deoxynucleoside triphosphates), the precursors for DNA synthesis. By maintaining the pool of dNTPs very low, SAMHD1 starves the virus of a building block that is essential for its replication.This is a great mechanism of defense because macrophages do not divide, thus do not replicate their nuclear DNA and are not affected by dNTPs starvation. We have also demonstrated that the HIV-2/SIV virus uses its Vpx protein to thwart the activity of SAMHD1 and thus to increase the intracellular pool of dNTPs.
AL: Outside HIV, what is the ‘physiological’ role of SAMHD1?
FMG: The ‘physiological’ role of SAMHD1 could be precisely to be a restriction factor. Recent work shows that SAMHD1 has evolved over 60 million years to probably adapt to constraints exerted by viruses (5, 6). To maintain a SAMHD1 activity makes sense in macrophages, which are specialized in destroying foreign pathogens. Outside HIV, SAMHD1 has been involved in an autoimmune disease: patients harboring mutations in SAMHD1 develop the Aicardi-Goutière syndrome (AGS), which is characterized by increased interferon production. Whether this role of SAMHD1 in AGS is linked to its function as a restriction factor remains to be investigated. Also it will be important to determine whether SAMHD1, through its ability to lower the levels of dNTPs, exerts a role in maintaining a quiescent state versus a proliferating state.
AL: If I understand well, SAMDH1 in HIV-1 infection at the dendritic cell level impairs the innate immune response and the mounting of a CD4 specific immune response against the virus?
FMG: SAMHD1 is not counteracted by HIV-1. As a result, dendritic cells are very poorly infected by HIV-1. Whether the presence of SAMHD1 (or the lack of Vpx) provides a selective advantage to the virus by limiting the infection is questionable. Treatment of DC with Vpx enhances IFN production after HIV-1 infection, which might look consistent with the overproduction of IFN in AGS, however lets note that cells producing IFN in AGS are not DC, macrophages or any immune cells (7). In addition, it is hypothesized that IFN production in the presence of Vpx is caused by activation of a cryptic sensor, which acts at the level of newly synthesized viral proteins, while SAMHD1 is supposed to act in the early phase of the infection before neo-synthesis takes place. Thus whether SAMHD1 impairs the innate immune response in HIV-1 infection at the dendritic levels remains to be investigated.
AL: Regarding macrophages, does SAMHD1 favors the persistence of HIV-1 in them?
FMG: SAMHD1 is active against HIV-1, though SAMHD1 does not totally stop the virus in macrophages. How the virus circumvents the presence of SAMHD1 in these cells is presently unknown. Once the viral DNA is synthesized and integrated into the host DNA, there is no reason for SAMHD1 to play a role, except maybe if the low dNTP concentration of the macrophage is sensed by the virus as a kind of signal for staying hidden in the cell.
AL: Is there a role for SAMDH1 in HIV-1 infection in other cells than dendritic cells and monocytes-macrophages?
FMG: SAMHD1 does not appear to be a barrier to HIV infection in actively replicating T cells. Either the catalytic activity of SAMHD1 is regulated in these cells to maintain the enzyme inactive or the rate of dNTP production is sufficient to replenish the dNTP pool. Future work is needed to investigate whether SAMHD1 plays a role in CD4+ quiescent cells, which are highly resistant to HIV infection.
AL: What could potentially be the therapeutic consequences of your research? Are they more prone to lead to new strategies to prevent HIV-1 transmission, or to fight against persistent HIV-1 in patients already on antiretrovirals?
FMG: I'm not sure yet about the therapeutic consequences of our research. Whether targeting SAMHD1 activity could lead to new strategies to prevent HIV infection is uncertain: first actively dividing T cells do not care about SAMHD1, second a strategy aimed at depleting the dNTP pool would be very deleterious not only for the virus but also for the cell. Nonetheless the study of the regulation of SAMHD1 activity is important to identify the pathways of cell resistance to HIV and to try to manipulate them. Above all, I believe our findings may help to understand why anti-HIV drugs are more effective than others and why their effectiveness depends on the environment (lets think that some nucleoside reverse transcriptase inhibitors are nucleoside and nucleotide analogues which inhibit reverse transcription by being incorporated in the newly synthesized viral DNA as faulty nucleotides).
AL: Could these discoveries have implications in other infectious diseases than HIV?
FMG: SAMHD1-mediated depletion of the intracellular dNTP pool provides a means by which the cell establishes an antiviral state without the need for an inhibitor that interacts directly with a specific viral component. Thus, this mechanism may serve to restrict a diverse range of retroviruses. In fact, all pathogens that do replicate through a DNA intermediate need to access to dNTP and may be sensitive to SAMHD1, lets take as example herpes viruses …
*Team Virus-Cell Molecular Interferences, Dept Cell Biology and Host-Pathogen Interactions, Building G. Roussy, Institut Cochin-Inserm U1016, 27 rue du Fg St Jacques, 75014 Paris, France
1-Laguette N, et al. Nature 2011; 474: 654-57
2-Hrecka K, et al. Nature 2011; 474: 658-61
3-Lahouassa H, et al. Nature Immunology 2012, published ahead of print; doi:10.1038:ni.2236
4-Laguette N, Benkirane M. Trends in immunology 2012; 33: 26-33
5-Laguette N, et al. Cell Host and Microbe 2012; 11: 1-13
6-Lim ES, et al. Cell Host and Microbe, 2012; 11
7-Manel N, et al. Nature 2010; 467, 214-217
Key words: SAMHD1, dendritic cells